The use of roentgenographic (x-ray) techniques to assist in the diagnosis of medical problems is well known and long established. For example, the diagnosis of fractures, arthritic conditions and other problems associated with the skeletal system is a routine and highly effective practice. Chest x-rays to provide early detection or confirmation of lung and heart disease are also routinely done.
The use of x-rays for the purpose of visualizing these organs is facilitated because there are sufficient differences in the densities of air, bone and soft tissue to produce an image on the x-ray film. However, the performance of an x-ray on abdominal organs can be impractical, if not impossible, because the densities of these organs are so similar that a satisfactory image cannot be obtained.
Notwithstanding the fact that an organ may not be visualized on x-ray, in many instances radiological techniques of diagnosis can still be accomplished through the use of contrast agents. Ideally, such an agent, which contains a substance denser than the adjacent tissues is administered to the patient in a manner which causes the agent to be distributed throughout the organ of interest.
Among the organs commonly examined by x-ray using contrast agents is the gastro-intestinal (GI) tract. The most widely used contrast agent for the GI tract, but by no means an ideal one, is barium sulfate administered orally or rectally as a suspension. The suspensions, however have limited stability even with stabilizers, have poor palatability and are constipating. Furthermore, in the upper GI tract, the suspensions lack homogeneity, becoming flocculent under the influence of gastrointestinal secretions, and do not adhere well to mucus membranes. Barium sulfate is also highly radio-opaque to x-ray and, as a result, a segment of small bowel or colon underlying another segment is obscured because of inadequate penetration by the x-ray radiation. When given orally, barium sulfate preparations are useless as an aid in examination of the colon as no coating of the mucosa occurs, the barium sulfate forming irregular clumps with fecal material. Furthermore, when administered as an enema, barium sulfate suspensions in the presence of fecal material show the same tendencies to flocculate and to coat the mucosa poorly.
Aqueous solutions of suitable radio-opaque molecules have been proposed as contrast agents for use in the GI tract and are less constipating than barium sulfate preparations. However, they are even less palatable than barium preparations and have other substantial deficiencies which have prevented them from gaining acceptance for that purpose. For example, they are hypertonic and highly irritating to the GI tract and are even considered to be hazardous to patients in the pediatric age group. They are also poor contrast agents in the GI tract, exhibiting relatively low radio-density which is made worse by osmotic dilution. The solutions, being water soluble, produce little or no mucosal coating as well.
Another class of contrast agents used for x-ray studies are oily organic substances containing iodine to confer radio-opacity. Among these may be mentioned Ethiodol (the iodine addition product of a mixture of ethyl esters of oleic, linoleic and linolenic acids obtained from poppyseed oil), Lipiodol (the iodine addition product of glyceryl esters of oleic, linoleic and linolenic acids), Angiopaque (ethyliodosterate), the isobutyl ester of diiodobehenolic acid and iodohexadecane. It will be recognized that these agents, but for iodohexadecane, are the product of adding iodine to the olefinic sites of esters of long chain (18-22 carbon atoms) unsaturated fatty acids. These substances have found no application in the GI tract because, being oily, they are not miscible with aqueous GI contents and do not coat the mucosa.
Emulsions of this class of contrast agents have been proposed for use in the GI tract, but pose substantial problems of toxicity. Teplich used emulsions of Ethiodol. See Teplich et al., Radiology, 82, 478 (1964). Reportedly, emulsions in which the particle size had been reduced to less than 0.3 micron gave good contrast visualization in the small intestine of dogs used as test subjects. In those tests, however, 50-70% of the oil was absorbed from the GI tract of the animals. Between 20-57% of the oil was eliminated by kidney function but the balance was stored in the body, posing the threat of a toxic reaction. Teplich et al. performed some clinical trials with human test subjects without reporting any data, but the results were such that the authors concluded that "an emulsion of a completely non-absorbable" radio-opaque substance "might" be ideal for use in the GI tract. On the other hand, the result of emulsifying an oil to improve its performance as a contrast agent also reduces its particle size which increases its absorbability and potential toxicity. In any case, emulsions of Ethiodol have not gained acceptance for use in the GI tract notwithstanding the well known shortcomings of barium sulfate preparations.
The use of an aqueous emulsion comprising 50% by volume of iophendylate "sparingly in the examination of the upper gastrointestinal tract" has been reported to produce results no better than that achieved using conventional materials. See Pirkey et al., Radiology, 55, 89, 92 (1950).
From the foregoing, it will be apparent that there has gone unfilled a long felt need for a method of radiological examination of the GI tract which employs a contrast agent that is convenient to use without inflicting discomfort on the patient or posing substantial toxicity problems and which coats the mucosa well, is stable in the GI tract and, at the same time, exhibits satisfactory radio-opacity and permits transradiation to permit visualization of underlying bowel segments.